Our overall long-term goal is to determine the etiology of the common and complex (multifactorial) disease, venous thromboembolism (VTE), by focusing on genetic and environmental factors that increase the risk of VTE, and the interactions among these factors. VTE is a common disease with over 900,000 incident or recurrent events in the U.S. annually;of these, almost one-third are fatal. To improve survival and avoid complications, VTE must be prevented. However, previous efforts to prevent VTE have been stymied because most individuals with known environmental (clinical) risk factors for VTE do not develop VTE. We hypothesize that, among those exposed to a clinical risk factor(s), a genetic predisposition distinguishes those who do from those who do not develop VTE. In support of this hypothesis, we have shown that VTE segregates in families due to heritability. VTE follows a complex mode of inheritance involving polygenes and environmental exposure. Our specific aims are: (1) to perform a genome wide association (GWA) screen and analysis using the 1M SNP platform specified by NHGRI genotyping facilities;(2) to test a)whether environmental exposures modify the observed relationship between genotype and VTE (geneenvironment interaction);and b) whether gene-gene interactions influence susceptibility to VTE;and 3) to test whether SNPs associated with VTE are located within or adjacent to genes that are functionally linked using pathway analysis. We currently have stored DNA samples from 829 VTE cases and 478 controls that are available for sharing with NHGRI, and by July 1, 2008, we project that we will have DNA samples from 1300 cases and 1300 controls. For all cases and controls, data on environmental exposures that are independent risk factors for VTE were collected with a standardized instrument. These data are stored in a SAS database by unique patient study number identifier and can be easily and rapidly shared. Using state of the art statistical genetic methods, we will identify genetic variants associated with VTE, including interactions. We will make the resulting data rapidly and widely available for research use and work collaboratively to share experience and expertise across participating biorepositories. Our results will have potentially great clinical utility by allowing physicians to stratify patients exposed to clinical risk factors into high- and low-VTE risk, identify unexposed patients at risk, and better target prophylaxis.